Oxo-M and 4-PPBP induction of tenogenic differentiation of perivascular tendon stem cells

Abstract

Provided herein are compositions including oxotremorine (e.g., oxotremorine methiodide or Oxo-M) and 4-PPBP (e.g., 4-PPBP maleate). Also provided are methods of treating a connective tissue defect in a subject with oxotremorine and 4-PPBP. In addition, provided are scaffolds and methods of making same that include multiple fibers that include Oxo-M, 4-PPBP, and optionally icariin or kartogenin.

What is claimed is: 
     
       1. A composition comprising oxotremorine M (Oxo-M) and PPBP maleate (4-PPBP). 
     
     
       2. The composition of  claim 1 , wherein the concentration of Oxo-M ranges from 10 μM to 100 mM. 
     
     
       3. The composition of  claim 2 , wherein the concentration of Oxo-M ranges from 100 μM to 10 mM. 
     
     
       4. The composition of  claim 3 , wherein the concentration of Oxo-M is 1 mM. 
     
     
       5. The composition of  claim 1 , wherein the concentration of 4-PPBP ranges from 100 nM and about 1 mM. 
     
     
       6. The composition of  claim 5 , wherein the concentration of 4-PPBP ranges from 1 μM and about 100 μM. 
     
     
       7. The composition of  claim 6 , wherein the concentration of 4-PPBP is 10 μM. 
     
     
       8. The composition of  claim 1 , wherein the concentration of Oxo-M is 1 mM and the concentration of 4-PPBP is 10 μM. 
     
     
       9. A pharmaceutical composition comprising:
 oxotremorine M (Oxo-M); 
 PPBP maleate (4-PPBP); and 
 a pharmaceutically acceptable excipient. 
 
     
     
       10. The pharmaceutical composition of  claim 9 , wherein the concentration of Oxo-M is 1 mM and the concentration of 4-PPBP is 10 μM. 
     
     
       11. The composition of  claim 1  further comprising a matrix material, a surgical adhesive, or a fibrin glue. 
     
     
       12. The composition of  claim 1  further comprising an antibiotic, an anti-inflammatory, a cytokine, a growth factor, or a stem cell. 
     
     
       13. The composition of  claim 1 , wherein said Oxo-M and said 4-PPBP are encapsulated in a microsphere. 
     
     
       14. A method of treating a connective tissue defect in a subject, the method comprising:
 administering a therapeutically effective amount of the composition of  claim 1  to said subject. 
 
     
     
       15. The method of  claim 14 , wherein said connective tissue defect comprises a tendon injury or a ligament injury. 
     
     
       16. The method of  claim 15 , wherein said connective tissue defect comprises a tendon injury. 
     
     
       17. The method of  claim 16 , wherein said tendon injury is a patellar tendon injury, an Achilles tendon injury, a rotator cuff injury, or lateral epicondylitis. 
     
     
       18. The method of  claim 14 , wherein said subject is a human subject. 
     
     
       19. A kit comprising a first container containing Oxo-M and a second container containing 4-PPBP. 
     
     
       20. The kit of  claim 19 , further comprising a third container containing a matrix material, a surgical adhesive, or a fibrin glue. 
     
     
       21. The kit of  claim 19  further comprising an antibiotic, an anti-inflammatory, a cytokine, a growth factor, or a stem cell.